Dr. Waldmann's studies have focused on the role played by the IL-2-IL-2R and IL-15-IL-15R systems in normal and abnormal T-cell function and in the use of these insights to develop IL-2R and IL-15R directed therapies for leukemia, autoimmune disease, and to prevent allograft rejection. As part of his studies of HTLV-I-associated adult T-cell leukemia (ATL), Waldmann co-discovered a cytokine, IL-15, that stimulates T-cell proliferation, is necessary for NK cell development, and is critical for the maintenance of CD8 memory T-cells. There is multifaceted control of IL-15 expression including transcriptional control mediated by interferon, IRF-1 and NFkB, as well as regulation at the levels of translation and intracellular trafficking of the cytokine. Two alternative complex signal peptides direct IL-15 either to the nucleus or to the secretory pathway. IL-15 utilizes two distinct cell surface receptors and signaling pathways. In T- and NK-cells the IL-15 receptor involves the private IL-15Ra subunit as well as IL-2Rb and gc shared with IL-2. As a consequence of this sharing of receptors, IL-2 and IL-15 also share some functions, especially in innate NK-mediated immunity. However, as supported by observations in an IL-15 transgenic mouse developed in the Waldmann lab, in adaptive immunity the two cytokines have distinct and competative functions. IL-2 is a critical factor in activation-induced cell death (AICD) leading to the death by suicide of self-reactive lymphocytes. IL-2 also inhibits the persistence of memory phenotype CD8 cells. Thus IL-2 favors peripheral tolerance to self antigens. In contrast, IL-15 inhibits AICD and facilitates the development and persistence of CD8 memory phenotype T-cells. Thus IL-15 favors the persistence of lymphocytes, especially those involved in the memory response to pathogens. This carries with it the risk that is realized that disorders of IL-15 expression would lead to the development of inflammatory autoimmune diseases. For example, the Waldmann lab has demonstrated a role for IL-15 and its receptor in HTLV-I-associated ATL and tropical spastic paraparesis (TSP). Spontaneous proliferation of T cells ex vivo and TSP and chronic ATL was abbrogated by the simultaneous addition of antibodies to IL-2 and IL-15 receptors supporting the view that there are autocrine-stimulating loops involving these cytokines and their receptors in this disease. The number of antigen (aa 11-19 of HTLV-I-encoded tax protein) reactive memory CD8 cells are exceptionally high in the circulation of patients with TSP. The addition of antibodies to IL-15 ex vivo to such peripheral blood mononuclear cells leads to the rapid (within 2 days) disappearance of these antigen-specific memory CD8 cells that participate in the pathogenesis of the disease. One of the most critical contributions of the Waldmann lab was the recognition that IL-2R and IL-15R represent extraordinarily useful therapeutic targets. The scientific basis for this approach is that resting cells do not express the alpha subunit of IL-2R whereas this receptor subunit is abundantly expressed by malignant cells including leukemic cells in ATL. A model of human HTLV-I-associated ATL was established in immunodeficient mice that is being used to evaluate potential therapeutic agents. The FDA approved humanized anti-Tac (daclizumab, Zenapax) for use in humans to prevent acute kidney transplant rejection. Furthermore, Hu-anti-Tac therapy led to reduction in HTLV-I proviral load and spontaneous lymphoproliferation in TSP patients and provided effective therapy for intermediate and posterior uveitis. In a clinical trial involving 90Y-anti-Tac (anti-IL-2Ra) therapy for patients with HTLV-I-associated ATL, the Waldmann group observed a partial or complete remission in over 50% of patients. New agents under active development include humanized antibodies directed toward IL-2/15Rb) that block all IL-15 action. This antibody will be used in the treatment of human IL-2/15Rb)-expressing leukemia as well as inflammatory autoimmune disorders. Furthermore, there is a broad program directed toward the development of IL-2 and IL-15 receptor-directed monoclonal antibodies armed with alpha-emitting radionuclides (213Bi, 211At), geldanamycin linked to an anti-HER2 mAb, as well as small molecular weight inhibitors of the tyrosine kinase Jak3 and STAT5 which are required for IL-2, IL-4, IL-7, IL-9, and IL-15 action. Thus new insights concerning receptors and signaling pathways used by malignant cells taken in conjunction with the ability to produce humanized antireceptor antibodies armed with radionuclides are providing novel perspectives for the treatment of select neoplastic diseases, autoimmune disorders, and to prevent allograft rejection.